Basic research in biological rhythms can be related to affective illness with respect to (1) the inherent cyclicity of the illness (itself a type of biological rhythm) and (2) the involvement of disturbed circadian rhythms (24-hour cycles) in its pathophysiology. This project is designed to explore these connections by interrelating behavioral, physiological and biochemical changes observed (1) through the cycle of the illness and (2) through the course of the 24-hour day. Results to date indicate (1) that in a subgroup of female bipolar patients the natural rate or frequency of cycling between mania and depression is accelerated 4-fold by maintenance tricyclic anti-depressants. The effects of tricyclics on the frequency of free-running circadian activity rhythms in hamsters is currently under study. (2) depressive and manic patients show state-dependent phase shifts (changes in timing) of circadian rhythms in temperature, motor activity, sleep architecture and neurotransmitter metabolites; in this circadian desynchronization the rhythm is not "locked in" to the environmental 24-hour day-night cycle, but tends to drift in and out of phase. (3) In phase shift experiments it has been possible to switch patients out of depression by directly manipulating the timing of circadian rhythms by changing patient's sleep schedules.